Immunologic Tolerance: Definition & Example

Instructor: Bridgett Payseur

Bridgett has a PhD in microbiology and immunology and teaches college biology.

How does the immune system know to attack germs but to leave your own cells alone? Read this lesson to learn how immunological tolerance works and what happens when things go wrong.

What Is Immunological Tolerance?

You've no doubt heard the word ''tolerance'' before. It implies being accepting of something, even if you don't agree with it. So what does the immune system have to do with tolerance? What is the immune system, anyway?

The immune system is your body's defense against invading germs. Different components can recognize bacteria and viruses. These are considered ''non-self.'' The immune system can also recognize its own cells when there is a problem, such as virus-infected cells and cancer cells. These are considered ''altered self.''

So how does tolerance play into all of this? Immunological tolerance describes how the immune system is able to recognize the body's own healthy, normal cells, as ''good.'' This differentiation between self, non-self, and altered self helps the immune system attack the bad guys while sparing the good guys.

How Is Tolerance Developed?

Immunological tolerance is discussed in terms of lymphocytes, the immune cells that provide memory. The two main types of lymphocytes are B cells, which produce antibodies, and T cells, which help with other parts of the immune response.

How do lymphocytes learn to ignore body cells? It's a two-part process.

Central Tolerance

The first step is developing central tolerance. This is like high school for the lymphocytes. They will be tested to make sure they can ignore self-antigens, or markers that would be found on the body's own normal cells. An antigen is anything that is recognized by lymphocytes and generates an immune response. A self-antigen is then, simply, an antigen on the body's own normal cells.

Lymphocytes go to high school in their home towns. T cells mature in and learn central tolerance in the thymus, while B cells mature in and learn central tolerance in the bone marrow.

In developing central tolerance, a lymphocyte is tested to see whether it reacts to a self-antigen, or ignores it. The lymphocytes that respond to self-antigens are deleted, meaning they are killed off so they can't graduate. This process helps get rid of most of the lymphocytes that recognize self-antigens.

If the lymphocyte does not react with the self-antigen, then it is free to move on. However, if it does react with the self-antigen, it is deleted.
central tolerance

Peripheral Tolerance

Just as a student can't learn everything in high school, lymphocytes aren't able to learn everything when being tested for central tolerance. After they complete their first education, they're sent out into the world (the rest of the body) to continue learning.

Peripheral tolerance helps ensure that lymphocytes that have left the central location of the bone marrow or thymus continue to ignore self-antigens. Peripheral tolerance is a very competitive, out-of-state college.

Peripheral tolerance mostly involves T cells. While B cells are also affected by peripheral tolerance, it is to a much lesser extent. To understand why T cells are susceptible to peripheral tolerance, we need to understand how they get activated in the first place.

A T cell is activated when an antigen presenting cell (APC) presents antigens to the T cell. This is like a teacher giving a book to a student. The T cell will recognize the antigen and then react.

However, the T cell needs to see more than just the antigen to become activated. The APC also needs to have a signal that says, ''This antigen is bad! We need to attack it!'' Otherwise, the T cell doesn't know what to do. It's like the teacher telling the student which chapters to read in the book. The T cell needs directions.

APCs can only produce the ''danger'' signal if the antigen they are presenting is foreign or altered-self. If the antigen is from a normal body cell, the APC won't produce the danger signal.

What does this have to do with tolerance? Well, if a T cell recognizes an antigen but there is no danger signal, it is recognizing self-antigen. Because of the lack of danger signal, the T cell isn't activated. Instead, it becomes anergic, which means it stops working. It can no longer perform its basic functions or even reproduce. Depending on the circumstances, some T cells will be deleted (killed off) if they recognize self-antigens. In still other instances, the T cell might become a regulatory T cell, and help stop other self-reactive lymphocytes.

Regulatory T cells help maintain peripheral tolerance for all types of immune cells. They help remove and down-regulate self-reactive B cells, for example. They also help turn down damaging inflammatory signals when necessary.

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